Non-irritating benzoyl peroxide

ABSTRACT

Crystalline benzoyl peroxide particles having a particle size no greater than 25 microns and formed by wet milling in the absence of solvents and wherein the crystalline benzoyl peroxide is not irritating to the skin. A therapeutic or cosmetic composition comprising a water-based gel containing the crystalline benzoyl peroxide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application 61/347,912 filedMay 25, 2010, which application is hereby incorporated by reference inits entirety.

TECHNICAL FIELD

This disclosure relates generally to benzoyl peroxide, methods of makingbenzoyl peroxide particles, and compositions containing benzoyl peroxideparticles.

BACKGROUND

Benzoyl peroxide (“BPO”) has long been used for treatment ofdermatological lesions and is also known to be an effectiveanti-microbial and anti-keratolytic agent useful, for example, in thetreatment of acne. Benzoyl peroxide is a non-toxic, colorless, odorless,and tasteless crystalline solid with a molecular weight of 242.22 and amelting point of between about 103° and 106° C. Pure (98% active)benzoyl peroxide crystals are commercially available but are consideredexplosive. Hence special precautions must be taken when handling pureBPO during preparation, transportation, and storage. BPO is alsocommercially available as a 75% crystalline solid with 25% water and isavailable from a number of suppliers, primarily in the plasticsindustry.

Conventional BPO crystalline powder requires milling for several hoursin water through high shear mills to prepare a paste having crystalsthat are sufficiently fine to be of acceptable texture for preparingproducts for topical use. Such crystals are typically average at least20 microns. These BPO crystals may be used to treat dermatologicallesions. However, the BPO crystals contacting the skin may have adverseirritative effects. The BPO Monograph finalized Mar. 4, 2010 (75 FR9768) cites 47 FR 12430 at 12444 as disclosing that BPO “is known to bea skin irritant and sensitizer in humans.” These adverse effects appearto result, at least in part, from excessive concentrations of BPO atskin areas in contact with BPO particles. Methods for avoiding suchadverse effects, while still effectively utilizing BPO therapeutically,have been long-sought.

Certain prior attempts to create stable, pharmaceutically effective anddermatologically non-irritative BPO preparations have involved theproduction of minute BPO crystals. U.S. Pat. No. 4,401,835, issued toTarasoy, describes a method of preparing BPO crystals that are less thanten microns in size. The method includes the steps of: (1) preparing afirst solution comprising BPO and a precipitate promoting material; (2)adding the first solution to a second solution that causes the BPO toprecipitate as a fine crystalline dispersion; and (3) recovering the BPOcrystals which may be washed or used directly. The precipitate promotingmaterial is a solvent for BPO that is able to produce a solutioncontaining up to about 15% by weight BPO. In one case the solvent isdimethyl ether of 1,4:3,6-dianhydrosorbitol (dimethyl isosorbide) ortetrahydrothiophene-1,1-dioxide. The second solution is an aqueoussolution of a non-toxic dispersant which is non-reactive with BPO. Thisdispersant is a cellulose derivative or a surfactant (non-ionic oranionic). However, solvents used to prepare the BPO crystals may havesolvent residues that also irritate the skin. Hence it is desirable toprovide a solvent-free, irritation-free, BPO formulation.

SUMMARY

Aspects of the present invention are directed to crystalline benzoylperoxide particles having a particle size no greater than 25 microns andformed by wet milling in the absence of solvents; wherein thecrystalline benzoyl peroxide is non-irritating to the skin.

Other aspects relate to a therapeutic or cosmetic composition comprisinga water-based gel comprising crystalline benzoyl peroxide solvent-freeparticles having a particle size no greater than 25 microns, wherein thecrystalline benzoyl peroxide is non-irritating to the skin.

Further aspects relate to a method of preparing crystalline benzoylperoxide comprising: adding water to solid benzoyl peroxide; milling tobreak up agglomerates and form an aqueous benzoyl peroxide; adding adispersion system and mixing; adjusting the pH to 2.8 to 6.6; andmilling to a particle size not more than 25 microns.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It was discovered that BPO can be produced in a form that is devoid ofparticles greater than 25 microns and essentially free of solvents ofthe BPO. That is, the particles are not produced by dissolving in, andthen crystallizing from, solvents and thus do not contain solvents.Instead a process is used that disperses BPO in water as a vehicle toprepare the BPO crystals.

In accordance with aspects of the invention, a composition containingBPO can be formulated into a finished dosage form and placed intocontact with human skin or other tissue without causing significantirritation. The compositions containing this crystalline, fine,solvent-free, BPO can be dispersions or pastes depending on theconcentration of BPO. Consequently, the compositions provide excellentvehicles for use in cosmetic lotions, gels, and creams, pharmaceuticalpreparations, and cleansing products.

In accordance with an aspect of the invention, solid BPO raw material isadded to water and then milled to break up agglomerates. Sufficientwater is added to form a flowable dispersion. For example, 35 to 55%benzoyl peroxide is added to 35 to 60% water. The milling process istemperature controlled using a chiller system so that the batch does notexceed 30° C. When an in-line mill is used for the milling process theamount of milling is determined by calculating the amount of time tomake three complete theatrically passes through the mill for the entirebatch. Milling is performed by a rotor mill such as a Ross Mill.

A dispersion system is then added to the batch and mixed in. The amountof the dispersion system depends on the actual ingredients used, butgenerally with by 0.2 to 4 wt % of the composition. The pH is adjustedto 2.8 to 6.6, typically 5.5 to 6.0, with a suitable amount of analkaline agent such as, but not limited to, sodium hydroxide, potassiumhydroxide or calcium hydroxide. The batch is then run through a secondmill resulting in a fine particle size which is essentially free ofparticles greater than 25 microns. Milling is performed with a highpressure mill that forces the product through a small orifice causingparticle collisions resulting in a size reduction (e.g., a Sonic Mill),for example, and then it is drummed off. The product is pumped from themanufacturing vessel into drums or pails. The drums and pails are thensold to customers. It is essentially the packaging step for the product.The resulting gel contains BPO in the form of small particles of BPOdispersed in water.

BPO in general is a soft plastic-like material that gets tacky whenheated. It is preferable to avoid this tacky property. Therefore, thetemperature of the mixture generally should not exceed 30° C. Ifnecessary, various ingredients and/or batches should be cooled duringthe process.

The resultant BPO is devoid of particles greater than 25 microns, moreparticularly devoid of particles greater than 10 microns, and still moreparticularly devoid of particles greater than 5 microns, and still moreparticularly devoid of particles greater than 3 microns. In one aspect,the BPO has a mean particle size of 1 to 2 microns and, moreparticularly about 1.2 to 1.5 microns. The median particle size may beabout 0.06 to 0.70 microns, for example, 0.65 microns. In anotheraspect, 5% of the particles are 0.35 microns or less, and 95% of theparticles are 3.5 microns or less. The maximum particle size is 25microns, more particularly 20 microns, still more particularly 10microns, still more particularly 5 microns, and even more particularly 3microns. The particles should be larger than nano-sized (greater than0.10 microns) to reduce transdermal delivery.

The dispersant system typically contains suspending agent(s) gellingaid(s), buffering agent(s), defoamer(s), and/or dispersant(s) which areselected to be nonreactive with respect to benzoyl peroxide and nontoxicand therefore safe for topical application. The dispersant system doesnot contain a solvent.

Suitable suspending agents may include, but are not limited to,acrylates copolymer, acrylates/methoxy peg-15 methacrylate copolymer,acrylates/steareth-20 methacrylate crosspolymer, acrylates/vinylisodecanoate crosspolymer, acrylates/vp copolymer, acrylicacid/acrylamidomethyl propane sulfonic acid copolymer, acrylic acid/vpcrosspolymer, ammonium styrene/acrylates copolymer, ammoniumva/acrylates copolymer, bentonite, biotite, butyl babassuate, calciumlignosulfonate, c4-24 alkyl dimethicone/divinyldimethicone crosspolymer,chitosan lauramide succinamide, cobalt dna, coralline officinalispowder, corn starch/acrylamide/sodium acrylate copolymer, dehydroxanthangum, diallyloxyneohexyl zirconium tridecanoate, dehydrogenated tallowbenzylmonium hectorite, dimethicone crosspolymer, dimethiconol/Stearylmethicone/phenyl trimethicone copolymer, dimethylol urea/phenol/sodiumphenolsulfonate copolymer, dipentaerythityl pentaisostearate, disodiummethylene dinaphthalenesulfonate, disteardimonium hectorite,ditrimethylolpropane isostearate/sebacate, ditrimethylolpropanetriethylhexanoate, erythityl triethylhexanoate, ethylene/ma copolymer,ethylene/va copolymer, ethylhexyl hydroxystearoyl hydroxystearate, ethyltrisiloxane, feruloyl soy glycerides, glass, glass beads, hectorite,hydrogenated isocetyl olivate, hydrogenated lecithin, hydroxyethylacrylate/sodium actyloyldimethyl taurate copolymer, hydroxyethylpei-1000, hydroxyethyl pei-1500, hydroxypropyl starch,hydroxypropyltrimonium maltodextrin crosspolymer, isobutylene/macopolymer, isopropyl babassuate, isopropyl ester of pvm/ma copolymer,magnesium phosphate, maltodextrin, methacrylol ethyl betaine/acrylatescopolymer, methoxy peg-17/dodecyl glycol copolymer, methoxypeg-22/dodecyl glycol copolymer, methoxy peg-114/polyepsiloncaprolactone, methyl methacrylate, myristoyl/pca chitin, nitrocellulose,octyldodecyl/ppg-3 myristyl ether dimmer dilinoleate, peg-18 castor oildioleate, peg-150/decyl alcohol/smdi copolymer, peg-12 dimethiconecrosspolymer, peg-150 stearyl alcohol/smdi copolymer, pei-7, pei-10,pei-15, pei-30, pei-35, pei-45, pei-250, pei-275, pei-700, pei-1000,pei-1400, pei-1500, pei-1750, pei-2500, pei-14m, pentafluoropropane,perfluoronyl octyldodecyl glycol meadowfoamate, perlite,phosphonobutanetricacarboxylic acid, polyacrylamidomethylpropanesulfonic acid, polyacrylate-10, polyacrylate-11, polycaprolactone,polyethylacrylate, polyglyceryl-4 isostearate/laurate,polyhydroxystearic acid, polyxymethylene cyanoguanidine urea,polyperfluorethoxymethoxy peg-2 phosphate, polyvinyl imidazoliniumacetate, polyvinyl methyl ether, ppg-3 myristyl ether neoheptanoate,propylene glycol ricinoleate, pvm/ma copolymer, pvp, pvp/va/ltaconicacid copolymer, quaternium-18 bentonite, quatemium-18/benzalkoniumbentonite, quaternium-18 hectorite, quaternium-90 bentonite, rhizobiangum, silica, silica dimethicone silylate, silica dimethyl silylate,silica silylate, sodium acrylate/sodium acryloyldimethyltaurate/acrylamide copolymer, sodium acrylates/vinyl isodecanoatecrosspolymer, sodium acrylates/vinyl isodecanoate crosspolymer, sodiumacrylic acid/ma copolymer, sodium acryloyldimethyl taurate/acrylamide/vpcopolymer, sodium c4-12 olefin/maleic acid copolymer, sodium dextransulfate, sodium dimaltodextrin phosphate, sodium glycereth-1polyphosphate, sodium isooctylene/ma copolymer, sodium magnesiumfluorosilicate, starch hydroxypropyltrimonium chloride, stearalkoniumbentonite, stearalkonium hectorite, Stearyl/ppg-3 myristyl ether dimmerdilinoleate, stearylvinyl ether/ma copolymer,styrene/acrylates/acrylonitrile copolymer, styrene/acrylates/ammoniummethacrylate copolymer, styrene/ma copolymer, sucrose benzoate/sucroseacetate isobutyrate/butyl benzyl phthalate copolymer, synthetic ruby,synthetic ruby powder, tosylamide/epoxy resin, tosylamide/formaldehyderesin, tribenzoyl triricinolein, vp/dimethylaminoethylmethacrylatecopolymer, vp/eicosene copolymer, vp/hexadecene copolymer, vp/vacopolymer.

Suitable gelling agents may include, but are not limited to, alcohol,alcohol denat., benzyl alcohol, 1,2-butanediol, butoxydiglycol,butoxyethanol, butylene glycol, cd alcohol 19, ceteareth-22, c7-8isoparaffin, c8-9 isoparaffin, c9-11 isoparaffin, c9-13 isoparaffin,c9-14 isoparaffin, c10-11 isoparaffin, c10-12 isoparaffin, c11-14isoparaffin, decane, decene, deodorized kerosene, diethylene glycol,dimethyl ether, dimethyl isosorbide, dimethyl sulfone, dipropyleneglycol, dodecene, ethoxydiglycol, ethoxyethanol, ethyl perfluorobutylether, ethyl perfluoroisobutyl ether, ethyl trisiloxane, glycereth-7,glycereth-8, glycereth-12, glycereth-20, glycereth-26, glycereth-31,glycerin, glycofurol, glycol, heptane, hexadecene, hexane,1,2,6-hexanetriol, hexyl alcohol, hexylene glycol, isobutoxypropanol,isopentane, isopropyl alcohol, methoxydiglycol, methoxyethanol,methoxyethanol acetate, methoxyisopropanol, methyl hexyl ether, methylperfluorobutyl ether, methyl perfluoroisobutyl ether, octadecene,octane, pentane, polyglyceryl sorbitol, propanediol, propyl alcohol,propylene carbonate, propylene glycol, sd alcohol 1, sd alcohol 3-a, sdalcohol 3-b, sd alcohol 3-c, sd alcohol 23-a, sd alcohol 23-f, sdalcohol 23-h, sd alcohol 27-b, sd alcohol 30, sd alcohol 31-a, sdalcohol 36, sd alcohol 37, sd alcohol 38-b, sd alcohol 38-c, sd alcohol38-d, sd alcohol 38-f, sd alcohol 39, sd alcohol 39-a, sd alcohol 39-b,sd alcohol 39-c, sd alcohol 39-d, sd alcohol 40, sd alcohol 40-1, sdalcohol 40-b, sd alcohol 40-c, sd alcohol 46, sorbeth-6, sorbeth-30,sorbeth-40, tetradecene, triethylene glycol, turpentine.

Suitable defoamers may include, but are not limited to, alcohol, alcoholdenat., behenyl methacrylate/ethylamine oxide, methacrylate copolymet,bisphenylhexamethicone, cetyl dimethicone, c12-14 sec-pareth-5,dimethicone, dimethicone silylate, dimethiconol, diphenyl dimethicone,diphenylsiloxy phenyl trimethicone, disiloxane, fluoro c2-8alkyldimethicone, hexadecyl methicone, hexyl alcohol, isopropyl alcohol,laureth-5 butyl ether, peg/ppg-8/26 dimethicone, peg/ppg-12/16dimethicone, peg/ppg-12/18 dimethicone, peg/ppg-16/8 dimethicone,petroleum distillates, phenethyl disiloxane, phenyl dimethicone, phenyltrimethicone, polysilicone-1, polysilicone-2, polysilicone-7,polysilicone-8, polysilicone-10, propyl alcohol, silica dimethiconesilylate, silica silylate, dimethicone, trimethylsiloxysilicate,trimethylsiloxysilicate/dimethicone crosspolymer, triphenyltrimethicone, trisiloxane.

Suitable buffering agents may include, but are not limited to, aluminumglycinate, aluminum lactate, ammonium acetate, ammonium carbonate,ammonium hexafluorophosphate, ammonium lactate, ammonium molybdate,ammonium phosphate, ammonium vanadate, boric acid, calcium carbonate,calcium phosphate, clay minerals, cyclohexylamine, decapeptide-7,diammonium citrate, diammonium phosphate, diethanolamine bisulfate,diethylamine, diethyl ethanolamine, disodium fumarate, disodiumphosphate, disodium pyrophosphate, ectoin, ethanolamine hcl, glycine,hydroxyethylpiperazine ethane sulfonic acid, lauryl p-cresol ketoxime,lithium fluoride, magnesium acetate, magnesium lactate, mes-borate,methoxy peg-114/polyepsilon caprolactone, mipa-borate,phosphonobutanetricarboxylic acid, potassium acetate, potassiumbicarbonate, potassium biphthalate, potassium citrate, potassiumlactate, sodium acetate, sodium aluminate, sodium aluminum lactate,sodium bicarbonate, sodium citrate, sodium fumarate, sodium humate,sodium lactate, sodium phosphate, sodium silicate, sodium succinate,sodium trimetaphosphate, tetrapotassium pyrophosphate, tetrasodiumpyrophosphate, trisodium sulfosuccinate, urea, zinc glycinate, zinchexametaphosphate.

Suitable dispersants may include cellulosic derivatives and surfactants,including both anionic surfactants and nonionic surfactants, inorganiccolloidal materials, and carboxyvinyl polymers (Carbomer). Thedispersant may comprise cellulose ethers and cellulose esters such ascarboxymethyl cellulose, hydroxyethyl cellulose, orhydroxypropylmethylcellulose; polysaccharide gums such as xanthan gums,guar gums, carrageenan gum, modified starches such as the modifiedpotato starch and the like, polyacrylamides such aspolyacrylamide/C13-14 isoparaffin/laureth-7 mixture, a mixture of sodiumacryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80; acrylicpolymers coupled to hydrophobic chains, such as the PEG-150/decyl/SMDIcopolymer, aluminum/magnesium silicate, polyvinyl alcohol, polyethyleneoxides, propylene glycol alginates or mixtures thereof. Particulardispersants include 1,3 Propanediol and sodium dioctyl sulfosuccinate.

The final pH of the gel or dispersant containing BPO is 2.8 to 6.6,typically 5.5 to 6.

The BPO compositions disclosed herein provide several advantages overprior compositions that are not made with the disclosed BPO particlesize in accordance with the disclosed process conditions. The instantcompositions are less irritating or non-irritating and less sensitizingor non-sensitizing than compositions made using larger particle size BPOor compositions containing BPO solvents. The compositions are also moreeffective and/or can be applied in amounts that are more effective inrelation to killing p.acnes and related bacteria. They can also beformulated to exhibit less tendency to cause de-pigmentation (bleachingeffect) of the skin.

The BPO can be added to other ingredients or vehicles often used incosmetic products, e.g., emulsions, lotions, creams or gels at lowtemperatures to provide finished products.

In one aspect, a gel former pre-mix is prepared by adding an appropriatequantity of water to a side mixing tank, adding the gel former, and thenallowing the gel-former to completely wet-out. After wet-out, the gelformer is mixed until the gel former is completely hydrated. Mixing iscontinued until the gel-former is added to the main batch.

A main batch is formed by, for example, adding water, sodium citrate,defoamer, dactyl sodium sulfosuccinate, and propanediol to a main mixingtank and mixing until uniform. The main batch may be re-circulated witha Ross mill. Raw BPO is added to the main batch with re-circulation andmilling. After all of the BPO is added, the Ross mill is shut off andthe gel former pre-mix is added to the main batch and mixed until thegel former is uniformly distributed through the batch. Sodium hydroxideis added to the main batch at a sufficient quantity to neutralize thedispersant and obtain the desired pH. The main batch is run through ahomogenizer and filled into containers.

In these processes, the BPO is never in contact with substantial heat;thus the possibility of decomposition or fire is greatly reduced. TheBPO compositions disclosed herein are also more stable and safer fortransportation as determined by Department of Transportation (DOT)standards. That is, in the disclosed gel form, the likelihood of enoughBPO accumulating to become explosive or a fire hazard is reduced. WhileDOT regulations limit the maximum BPO concentration to 40% by weight,the compositions disclosed herein can be used in higher concentrationsbecause they have less tendency to agglomerate and therefore maintaintheir stability. Additionally, while certain known BPO gel compositionstend to harden or thicken upon storage, especially at lowertemperatures, the compositions disclosed herein do not tend to hardenand/or thicken to a lesser degree than known compositions. Testingincluded attempts to ignite the material, exposing the product toelevated temperatures (70° C. for 72 hours), and impact and frictiontesting. In all cases the 40% material was unreactive and stable.

Example 1

The following BPO composition was prepared by combining water, BPO,other ingredients, milling, and then adding a neutralizing agent.

Component Purpose Percent range Water Vehicle 42-46% Raw benzoylperoxide Active 52-54% Sodium Citrate Buffer 0.9-1.1% Starsil AF30FCDefoamer 0.09-0.11% Gemtex SC-70-P Dispersing Aids  1.3-0.71% ZemeaCarpobol Ultrex 10 Suspending Aid 0.35-0.45% Sodium hydroxideNeutralizing agent To spec Starsil AF3OFC, Starchem, LLC: dimethicone,silica, sorbitan stearate, sorbitan stearate, PEG-40, xanthan gum.Gemtex SC-70-P, Innospec Active Chemicals, LLC: sodium dioctylsulfosuccinate. Zemea, DuPont, Tate & Lyle Bioproducts: 1, 3 PropanediolCarpobol Ultrex 10, Lubrizol: Carbomer

Accelerated stability studies at 40° C. and 75% relative humidity todetermine whether there is degradation of the BPO over time.

Initial 43.04% BPO 2 months 40.07% BPO 3 months 40.76% BPO 4 months40.69% BPO 6 months 40.72% BPO

Example 2

Twenty-five subjects ages 20-65 were requested to bathe or wash as usualbefore arrival at the facility. Qualified subjects were then preparedfor patch application by having the test sites wiped with alcohol andair-dried. Patches dosed with 0.2 ml or 0.2 g of a 10% active BPOdispersion (prepared from a 40% dispersion as the source for the BPO),patches dosed with positive (1.0% Sodium Lauryl Sulfate (SLS) solution),and patches dosed with negative (undosed semi-occlusive patch) controlswere then applied directly to the skin of the infrascapular regions ofthe back, to the right or left of the midline on every day of the weekfor the first 12 days and the subject was dismissed with instructionsnot to wet or expose the test area to direct sunlight. Patches wereapplied for approximately a 24 hour period, then removed and discardedby the subject approximately two hours prior to grading. All inductionpatches were applied to the same sites unless the degree of reaction(cumulative grade 3) to a material or the adhesive necessitated removal.The skin adjacent to the patches was marked using a surgical marker orother suitable marking pen. Prior to each reapplication, the test siteswere evaluated. At the final visit, no patches were applied and thepatch sites were graded. Skin responses were evaluated according to thefollowing scale by a technical associate of AMA Laboratories, Inc.(scorer) trained in the evaluation of skin using consistent adequatelighting from a 60-watt incandescent blue day light bulb to illuminatethe patch area. All reasonable attempts were made to ensure that thesame individual did all of the scoring of reactions to the test articlesduring the course of the study, and was blinded to the treatmentassignments and any previous scores.

Scoring of Test Sites:

-   -   Skin reactions at the patch sites were assigned using the        following scale:    -   0 No evidence of irritation    -   1 Minimal erythema, barely perceptible    -   2 Definite erythema, readily visible; or minimal edema; or        minimal papular response    -   3 Erythema and papules    -   4 Definite edema    -   5 Erythema, edema, and papules    -   6 Vesicular eruption    -   7 Strong reaction spreading beyond test site    -   Effects on superficial layers of the skin were scored as        follows:

A Slight glazed appearance

-   -   B Marked glazing    -   C Glazing with peeling and cracking    -   D Glazing with fissures    -   E Film of dried serous exudate covering all or portion of the        patch site    -   F Small petechial erosions and/or scab

For cumulative scoring purposes, any score of 3 or higher was consideredto be a 3 for the remainder of the test, even though applications forthat test site were discontinued. The actual patch test scores were thecombination of a numerical and/or letter score consistent with thedefinitions given in the scoring scale. Scores containing letter gradeswere converted into numerical equivalents as follows: A=0, B=1, C=2, andD, E, and F=3. These equivalents were considered additive to anynumerical score (e.g., 2C=2+2=4).

All scorers were required to take and pass a visual discriminationexamination conducted by a board certified ophthalmologist using theFarnsworth-Munsell 100 Hue test. This test, which determines a person'sability to discern color against a black background, was modified toincorporate a flash tone background (instead of black) to simulate theactual use conditions.

The test material was applied five days weekly for 12 days to the samesite, or until irritation scores of 3 were observed. In this caseapplication of the test sample is discontinued and the score attained isentered for the balance of the 12 day test. New test patches wereapplied to the test sites after visual evaluation.

Statistics and Data Management:

To obtain classifications of the test materials, subject scores weretotaled for each test site. A standardized interpretation system forbase (n=10) irritation scores during induction at 14 days wasestablished by Berger and Bowman (Berger R. S, and J. P. Bowman, Areappraisal of the 21-day cumulative irritation test in man, J.Toxicol.—Cut. & Ocular Toxicol. 1 (2), 109-115, 1982). This system hasbeen adjusted proportionally for 12 days of induction and for base(n=25). Categories were based on percentages of the maximum possiblescore for each test site. For the calculation of a total score, an upperlimit of 3 was used. For cumulative scoring purposes, any score of 3 orhigher was considered to be a 3 for the remainder of the test, eventhough applications for that test site are discontinued.

The following classification system was used evaluation of the results:

Description of Observed Score Indications from Test Response 0 to 70.71Mild material - no Essentially no evidence of experimental irritationcumulative irritation under the conditions of test (i.e., continuous atconcentration specified) >70.71 to 285 Probably mild in Evidence ofslight potential normal use for very mild cumulative irritation underconditions of test >285 to 640.71 Possibly mild in Evidence of moderatenormal use potential for mild cumulative irritation under conditions oftest 640.71 to 829.29 Experimental Evidence of strong potentialcumulative irritant for mild-to-moderate cumulative irritation underconditions of test >829.29 to 900 Experimental Primary Evidence ofpotential for irritant primary irritation under conditions of test

Mean cumulative irritation scores were compared among the sites usingtwo tailed Student's T-test with paired comparisons. All differenceswere considered significant at the p<0.05 level. The maximum potentialscore for a test material was calculated by multiplying the maximumpotential daily score (3) by the number of panelists completing thestudy by the number of days of evaluation (9). In the event of anadverse reaction, the area of erythema and edema was measured. The edemawas estimated by the evaluation of the skin with respect to the contourof the unaffected normal skin. Accompanying edema (swelling), if any, atany test site was recorded with an “e” and is described as mild,moderate or severe as compared with the normal surface of surroundingskin. Clients were notified immediately in the case of an adversereaction and determination was made as to treatment program ifnecessary.

The results of panelists treated with the test material exhibited totalcumulative irritancy score of 6. When compared to the negative controlsite—blank undosed semi-occlusive patch, which showed cumulativeirritancy score of 0 and the positive control, semi-occlusive patchdosed with one hundred (100) microliters of a 1.0% Sodium Lauryl Sulfate(SLS), which showed cumulative irritancy score of 78. The test materialpresented essentially no evidence of cumulative irritation under theconditions of test.

The BPO used herein is advantageous because, unlike the crystalsobtained by precipitation described in U.S. Pat. No. 4,401,835, the BPOparticles are obtained by finely milling the compound. Precipitation isdisadvantageous because it introduces solvents for the BPO that aredifficult to remove completely and that can sensitize and irritate theskin especially in the presence of the fine particle size BPO.Accordingly, whereas in accordance with U.S. Pat. No. 4,401,835, smallparticle size BPO is obtained by precipitation and introducing BPOsolvents that may enhance skin sensitivity and skin irritation, inaccordance with the invention, the BPO is obtained by milling in theabsence of BPO solvents to provide a product that is free of bothirritating large particles and solvent. The fine particle size of theinstant product and the absence of solvents is believed to make thematerial especially desirable for use in cosmetic products.

An additional characteristic of suspensions of BPO is the tendency forthe BPO particles to re-agglomerate. In using the dispersion systemdisclosed herein, there is a reduced level of re-agglomeration whichmanifests itself in the improved safety profile in regard to the resultsof the DOT testing. This effect will potentially allow for a moreefficient final product for topical use.

The low sensitivity and irritation experienced with the BPO of theinvention, makes it useful in certain applications where patients withsensitive skin were not able to use other forms of BPO. Because the BPOused herein is not an irritant or sensitizer, it can be used in caseswhere patients show irritation to other forms of BPO. It is furtherbelieved that the BPO disclosed herein can be used in cases ofclinically diagnosed sensitive skin. Similarly, patients exhibiting ahigh sensitivity to BPO who might not have been treatable with moreirritating BPO compositions may be treated using the BPO describedherein.

While the invention has been described with respect to specific examplesincluding presently preferred modes of carrying out the invention, thoseskilled in the art will appreciate that there are numerous variationsand permutations of the above described systems and techniques that fallwithin the spirit and scope of the invention as set forth in theappended claims.

What is claimed is:
 1. Crystalline, solvent-free, benzoyl peroxideparticles having a particle size no greater than 25 microns and formedby wet milling benzoyl peroxide consisting of solid benzoyl peroxide, inthe absence of solvents; wherein the crystalline benzoyl peroxide isnon-irritating to the skin.
 2. The benzoyl peroxide particles of claim 1wherein the particle size is not greater than 10 microns.
 3. The benzoylperoxide particles of claim 1 wherein at least 90% of the particles areless than 3.5 microns in size.
 4. The benzoyl peroxide particles ofclaim 1 wherein at least 95% of the particles are less than 3.5 micronsin size.
 5. The benzoyl peroxide particles of claim 1 wherein an averageparticle size is from 1 to 2 microns.
 6. A therapeutic or cosmeticcomposition comprising a water-based gel comprising crystalline,solvent-free, benzoyl peroxide particles having a particle size nogreater than 25 microns, and formed by wet milling benzoyl peroxideconsisting of solid benzoyl peroxide, in the absence of solvents;wherein the crystalline benzoyl peroxide is non-irritating to the skin.7. The composition of claim 6 wherein the particle size is not greaterthan 10 microns.
 8. The composition of claim 6 wherein at least 90% ofthe particles are less than 3.5 microns in size.
 9. The composition ofclaim 6 wherein at least 95% of the particles are less than 3.5 micronsin size.
 10. The composition of claim 6 wherein an average particle sizeis from 1 to 2 microns.
 11. The composition of claim 6 furthercomprising a dispersing system.
 12. The composition of claim 11 whereinthe dispersion system comprises at least one selected from the groupconsisting of suspending agents, gelling aids, buffering agents, anddispersants.
 13. The composition of claim 11 wherein the compositioncontains about 25 to 65% by weight benzoyl peroxide.
 14. A method fortreating skin lesions in a patient that exhibits acute sensitivity tobenzoyl peroxide which comprises applying to the lesions a therapeuticor cosmetic composition according to claim 6 in a pharmaceuticallyacceptable vehicle.